In nearly 200 youth, higher anandamide and lower 2-AG blood levels were associated with more severe anxiety, while increases in 2-AG during SSRI treatment predicted better treatment response.
Child psychiatrists, anxiety researchers, and anyone interested in biomarker-guided mental health treatment.
2-AG increases during SSRI treatment predicted better anxiety response
What the researchers found
After adjusting for BMI, age, sex, and time of day, higher AEA and lower 2-AG were associated with more severe anxiety symptoms. In a subsample of 41 adolescents with GAD in an 8-week RCT of escitalopram, greater increases in 2-AG from baseline were linked to improved treatment response, without changes in AEA.
Why it matters
If blood endocannabinoid levels can predict who will respond to anxiety treatment, they could become the first objective biomarkers for guiding psychiatric care in youth. The selective association of 2-AG (but not AEA) with treatment response suggests these two endocannabinoids play different roles.
The numbers in context
N = 199 youth (ages 9-17). RCT subsample: N = 41 (ages 12-17), escitalopram 15-20 mg/day for 8 weeks. BMI positively correlated with AEA. 2-AG negatively associated with age, female sex, and time of day. Higher AEA and lower 2-AG associated with greater anxiety severity.
How the study worked
Circulating AEA and 2-AG were measured in 199 youth aged 9-17 with varying anxiety levels. Anxiety was assessed using the SCARED questionnaire. A subset of 41 adolescents (12-17) with GAD participated in an 8-week randomized placebo-controlled trial of escitalopram, with endocannabinoid levels measured at baseline and during treatment.
What this study cannot tell us
Circulating endocannabinoid levels may not perfectly reflect brain levels. The RCT subsample is small (41 participants). Cross-sectional anxiety-endocannabinoid associations cannot determine causation. SCARED is a self-report measure.
How to read the evidence
Novel biomarker study combining observational data (N=199) with a subsample from an 8-week RCT (N=41). Moderate evidence given the small trial subsample.
When this study was published
Published in 2025 in Neuropsychopharmacology.
The bigger picture
The endocannabinoid system is emerging as a key regulator of anxiety across the lifespan. This study bridges basic neuroscience and clinical psychiatry by showing that the same endocannabinoid changes seen in animal anxiety models are measurable in the blood of anxious youth and respond to treatment.
Questions still open
- Could baseline 2-AG levels predict which anxious youth will respond to SSRIs before treatment begins? Do cannabis-using youth have altered endocannabinoid profiles that affect anxiety treatment?
Common questions
What are AEA and 2-AG?
Could this lead to a blood test for anxiety?
Read the original research
Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(10), 1606-1614
Citation
Marusak, Hilary A; Zundel, Clara G; Shakir, Tehmina; Ely, Samantha L; Carpenter, Carmen; Shampine, MacKenna; Tamimi, Reem; Matsko, Mariya; Rogers, Sarah; Losiowski, Jennifer; O'Mara, Emilie; Jaster, Alaina M; Sharma, Kamakashi; deRoon-Cassini, Terri A; Hillard, Cecilia J; Schroeder, Heidi K; Mills, Jeffrey A; Strawn, Jeffrey R; Barcelona, Jeanne. (2025). Circulating endocannabinoids in children and adolescents: associations with anxiety and the impact of selective serotonin reuptake inhibitors.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 50(10), 1606-1614. https://doi.org/10.1038/s41386-025-02155-7
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